Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human mesangial cells and induce interleukin-6 and plasminogen activator inhibitor-1 secretion

Bobst, Sol M.; Day, Mary Clare; Gilstrap, Larry C.; Xia, Yang; Kellems, Rodney E.

doi:10.1016/j.amjhyper.2004.10.002

Cited by 89 publications

(56 citation statements)

References 34 publications

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“…Activation of AT 1 receptors by these autoantibodies on various cell types provokes biological responses relevant to the pathophysiology of preeclampsia. [27][28][29][30][31][32] We report here that IgG from preeclamptic but not normotensive pregnant individuals stimulates sFlt-1 synthesis and secretion by pregnant mice, by human placental villous explants, and by cultured human trophoblasts. We show that these autoantibodies are capable of inducing endothelial dysfunction via sFlt-1 induction.…”

mentioning

confidence: 94%

Autoantibody From Women With Preeclampsia Induces Soluble Fms-Like Tyrosine Kinase-1 Production via Angiotensin Type 1 Receptor and Calcineurin/Nuclear Factor of Activated T-Cells Signaling

et al. 2008

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Abstract-Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Recent evidence indicates that maternal endothelial dysfunction in preeclampsia results from increased soluble Fms-like tyrosine kinase-1 (sFlt-1), a circulating antiangiogenic protein. Factors responsible for excessive production of sFlt-1 in preeclampsia have not been identified. We tested the hypothesis that angiotensin II type 1 (AT 1 ) receptor activating autoantibodies, which occur in women with preeclampsia, contribute to increased production of sFlt-1. IgG from women with preeclampsia stimulates the synthesis and secretion of sFlt-1 via AT 1 receptor activation in pregnant mice, human placental villous explants, and human trophoblast cells. Using FK506 or short-interfering RNA targeted to the calcineurin catalytic subunit mRNA, we determined that calcineurin/nuclear factor of activated T-cells signaling functions downstream of the AT 1 receptor to induce sFlt-1 synthesis and secretion by AT 1 -receptor activating autoantibodies. AT 1 -receptor activating autoantibody-induced sFlt-1 secretion resulted in inhibition of endothelial cell migration and capillary tube formation in vitro. Overall, our studies demonstrate that an autoantibody from women with preeclampsia induces sFlt-1 production via angiotensin receptor activation and downstream calcineurin/nuclear factor of activated T-cells signaling. These autoantibodies represent potentially important targets for diagnosis and therapeutic intervention. Key Words: preeclampsia Ⅲ renin-angiotensin system Ⅲ angiotensin receptor Ⅲ autoantibody Ⅲ angiogenesis Ⅲ cell signaling P reeclampsia is a pregnancy-specific syndrome of hypertension and proteinuria, resulting in substantial maternal and neonatal morbidity and mortality. 1 Although the underlying pathogenic mechanisms of the disorder are not well understood, preeclampsia is largely believed to be associated with uteroplacental ischemia and maternal endothelial cell dysfunction. [2][3][4][5] It is a widely held view that "toxic factors" secreted by the placenta into the maternal circulation are responsible for systemic endothelial dysfunction, hypertension, and multiorgan damage. 6 -11 Recent research has shown that soluble Fms-like tyrosine kinase-1 (sFlt-1) is 1 of the key "toxic factors" released by the placenta into the maternal circulation and that it contributes to the hypertension, proteinuria, and endothelial cell dysfunction associated with this disorder. 12-15 sFlt-1 is a soluble form of the vascular endothelial growth factor receptor that lacks the cytoplasmic tail and transmembrane domain but retains the extracellular ligand-binding domain (sFlt-1 is also named sVEGFR1).Therefore, sFlt-1 prevents circulating vascular endothelial growth factor and placental growth factor interactions with their proangiogenic receptors and functions as an antiangiogenic factor. The level of sFlt-1 in the plasma of women with preeclampsia is elevated in comparison with that in women...

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confidence: 94%

Autoantibody From Women With Preeclampsia Induces Soluble Fms-Like Tyrosine Kinase-1 Production via Angiotensin Type 1 Receptor and Calcineurin/Nuclear Factor of Activated T-Cells Signaling

et al. 2008

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“…69 Phosphorylation of ERK1/2 (extracellular signal-regulated kinase 1/2), induction of NADPH oxidase, phosphorylation of NF-κB (nuclear factor kappa light chain enhancer of activated B cells), and promoter activation in the nucleus have been all implicated in Ang II hypersensitivity in preeclampsia. 70 Studies in rats treated with L-NAME during pregnancy suggest that hypersensitivity to Ang II may be because of oxidative stress and reduced NO bioavailability. donors in pregnant rats treated with suramin that exhibit preeclampsia-like features such as hypertension, proteinuria, and intrauterine growth restriction.…”

Section: Angiotensin IImentioning

confidence: 99%

Maternal Vascular Physiology in Preeclampsia

Goulopoulou

2017

Hypertension

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“…PAI-1 plays a role in trophoblast invasion by inhibiting the urokinase-type plasminogen activator, resulting in decreased conversion of plasminogen to plasmin, decreased extracellular matrix digestion, and shallow trophoblast invasion. We have also shown that AT1-AA activate AT1 receptors on cultured human mesangial cells resulting in the stimulation of PAI-1 synthesis and secretion, a feature that may contribute to kidney damage leading to proteinuria, a hallmark manifestation of preeclampsia (9). Increased PAI-1 production by trophoblast cells, mesangial cells, and possibly other cell types may contribute to the hypercoagulation sometimes associated with preeclampsia.…”

Section: At1-aa May Contribute To Multiple Features Of Preeclampsiamentioning

confidence: 95%

Angiotensin Receptors, Autoimmunity, and Preeclampsia

Xia¹,

Zhou²,

Ramin

et al. 2007

The Journal of Immunology

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Preeclampsia is a pregnancy-induced hypertensive disorder that causes substantial maternal and fetal morbidity and mortality. Despite being a leading cause of maternal death and a major contributor to maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are poorly understood. Recent studies indicate that women with preeclampsia have autoantibodies that activate the angiotensin receptor, AT1, and that autoantibody-mediated receptor activation contributes to pathophysiology associated with preeclampsia. The research reviewed here raises the intriguing possibility that preeclampsia may be a pregnancy-induced autoimmune disease.

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Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human mesangial cells and induce interleukin-6 and plasminogen activator inhibitor-1 secretion

Abstract: Our findings suggest that a maternal autoantibody with the ability to activate AT(1) receptors may account for the development of renal damage seen in preeclamptic patients.

Cited by 89 publications

References 34 publications

Autoantibody From Women With Preeclampsia Induces Soluble Fms-Like Tyrosine Kinase-1 Production via Angiotensin Type 1 Receptor and Calcineurin/Nuclear Factor of Activated T-Cells Signaling

Autoantibody From Women With Preeclampsia Induces Soluble Fms-Like Tyrosine Kinase-1 Production via Angiotensin Type 1 Receptor and Calcineurin/Nuclear Factor of Activated T-Cells Signaling

Maternal Vascular Physiology in Preeclampsia

Angiotensin Receptors, Autoimmunity, and Preeclampsia

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